Treatment of patients at risk of rapid progression of osteoarthritis

Abstract

To provide treatment of patients at risk of rapid progression of osteoarthritis.SOLUTION: The invention pertains to active compounds, in particular FGF-18 compounds, for use in the treatment of patients affected with a cartilage disorder, preferably osteoarthritis (OA), in particular for the treatment of patients who are at risk of rapid progression of the disorder.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to active compounds, in particular FGF-18 compounds, for use in the treatment of patients suffering from cartilage disorders, preferably osteoarthritis (OA), especially in patients at risk of rapid progression of this disorder.

Background Art

[0002] Cartilage disorders broadly mean diseases characterized by the progression of metabolic abnormalities in connective tissue, and manifest as pain, stiffness, and limitation of movement in the affected body part. These disorders can be due to medical conditions or as a result of trauma or injury. Particularly included in cartilage disorders are osteoarthritis (OA), cartilage damage (including sports-related cartilage and joint injuries and surgical injuries such as microfractures). Mature cartilage has limited ability to repair itself. This is especially because mature chondrocytes have little ability to proliferate and there are no blood vessels. In addition, cartilage is not well nitrified and has a low oxygen pressure.

[0003] OA is a progressive cartilage disorder which in the early stages may have minor and asymptomatic structural changes in the joint but usually progresses to more advanced (moderate and severe) stages. The structural changes in OA are characterized by progressive erosion and loss of articular cartilage and the appearance or increase of symptoms of stiffness and pain. The most common way to classify osteoarthritis is by use of the Kellgren-Lawrence (KL) assessment scale, which is described herein. Briefly, the KL assessment scale defines five stages ("0": none, to "4": severe) based on X-ray analysis of the structural defects of the joint.

[0004] There are no commercially available therapeutic agents that can restore or delay cartilage damage (see Lotz, 2010). However, there are treatment options for managing clinical symptoms, which will likely vary depending on the severity or stage of this disease. Initial stage treatments typically include most physical therapies, lifestyle changes such as increased physical activity, and supportive devices. However, as osteoarthritis progresses to mild or moderate stages and clinical symptoms worsen, the use of analgesics (such as non-steroidal anti-inflammatory drugs) may be required. These are effective in relieving the pain, joint swelling, and inflammation associated with osteoarthritis, but their use may be limited by gastric irritation. In severe or late stages, more powerful analgesics may be useful, but in some cases, surgical procedures may still be necessary.

[0005] When surgical procedures are necessary, the standard procedures are age-dependent and range from total joint replacement, or transplantation of cartilage fragments, or bone marrow stimulation techniques (such as microfracture). Tibial or femoral osteotomy (shaving the bone to correct the balance of joint wear) may be useful in maintaining an active lifestyle and delaying the need for total joint replacement. Total joint replacement can relieve the symptoms of advanced osteoarthritis, but generally the patient needs to change their lifestyle and / or activity level. Replacing damaged cartilage (especially articular cartilage) caused by injury or disease is a major challenge for physicians, and the available surgical treatment procedures are not completely predictable and are considered to be effective for only a limited period. Microfracture is a common procedure that involves penetrating the subchondral bone to promote cartilage fixation by stem cell-derived bone marrow. However, this technique has been shown not to adequately repair cartilage defects, and the newly formed cartilage is mainly fibrous cartilage, resulting in insufficient or altered function and biomechanics. In fact, fibrous cartilage does not have the same durability and may not attach properly to the surrounding hyaline cartilage. For this reason, newly synthesized fibrous cartilage is more likely to break down (expected period: 5 - 10 years).

[0006] Therefore, the majority of younger subjects either do not seek surgical treatment or, upon counseling, defer surgical treatment as long as possible.

[0007] It is well known that the progression of the disease is inconsistent among patients with knee OA and that numerous factors are associated with the risk of rapid progression. The rate of joint space narrowing, i.e., the rate at which cartilage thinning occurs, is an excellent indicator of the progression of this disease, but data need to be collected over a period of time before any conclusions or predictions can be made. In clinical trials, several parameters measured at baseline, i.e., before any drug is administered, have been correlated with the risk of rapid progression of this disorder. In particular, OA that has been clearly shown to have KL grade 2 or higher OA by X-ray at baseline has been associated with the progression of this disorder (Guermazi et al., 2015). The joint space width (JSW) measured at baseline, particularly the medial compartment joint space width (mJSW), is considered a strong predictor inversely correlated with the progression rate of knee OA (Pelletier et al., 2007). Consistent with this, the value of the medial JSW at baseline is also a strong predictor of total knee replacement. In addition, there is evidence that knee pain is not only a consequence of the structural deterioration of osteoarthritis (OA) but also contributes to structural progression. Joint pain (which can be evaluated by the WOMAC index) has been further identified as another strong predictor of the structural progression of OA, and subjects experiencing persistent knee pain with a Kellgren-Lawrence grade of 2 or higher show an increased risk of progressive OA (Wang et al., 2018).

[0008] Patients at risk of rapid progression of this cartilage disorder may not be able to avoid surgical treatment, and relief from analgesics can only be found for a short period.

[0009] Therefore, there is a need for new treatment strategies that are thought to limit the structural progression of this disorder and, ideally, assist in the management of the increasing pain associated with OA, particularly for treating patients at risk of rapid progression of the cartilage disorder.

Summary of the Invention

[0010] The present invention relates to an active compound, preferably an FGF-18 compound, for use in the treatment of a subject having a cartilage disorder, wherein the subject exhibits a risk of rapid progression of said cartilage disorder. As defined in more detail herein, a patient is considered to exhibit a risk of rapid progression of a cartilage disorder when the patient exhibits a combination of the following two parameters: (a) a significant structural defect of a joint and (b) intolerable joint pain.

[0011] The present invention further relates to a method for treating a subject having a cartilage disorder, the method comprising a) determining whether the subject exhibits at least one significant structural defect of at least one joint, wherein the significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; and b) obtaining an assessment of the level of joint pain in the subject, wherein the level of joint pain is preferably evaluated based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score; and c) i. at least one significant structural defect of at least one joint and ii. intolerable joint pain selecting a patient having the same; and d) administering to the selected patient an active compound, preferably an FGF-18 compound.

[0012] The present invention further relates to a method of selecting a subject having a cartilage disorder for inclusion in a treatment or clinical trial using an active compound, based on their likelihood of being sensitive to said treatment, the method comprising a) determining whether the subject exhibits at least one prominent structural defect of at least one joint (wherein the prominent structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3); b) obtaining an assessment of the level of joint pain of the subject (wherein the level of joint pain is preferably assessed based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score); c) including the step of selecting the sensitive subject as being suitable for the treatment or clinical trial.

[0013] The present invention further relates to a method for determining a placebo effect in a clinical trial (preferably, the clinical trial relates to treating a cartilage disorder of a subject with an active compound), or a placebo effect during treatment of a cartilage disorder with an active compound. This method comprises: a) determining whether the subject exhibits at least one prominent structural defect of at least one joint (wherein the prominent structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3); b) obtaining an assessment of the level of joint pain of the subject (wherein the level of joint pain is preferably assessed based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score); c) including the step of determining the placebo effect from the results of step a) and step b).

[0014] Definitions

[0015] The term "bioactive compound" as used herein means a compound selected from the group consisting of, for example, an FGF-18 compound, a BMP-2 enhancer, a BMP-7 enhancer, a GDF-5 enhancer, an FGFβ enhancer, an FGF-9 enhancer, a SOX-9 enhancer, a TGFβ inhibitor, a Wnt inhibitor, an anti-MMP-13 inhibitor, an anti-ADAMTS4 inhibitor or an anti-ADAMTS5 inhibitor, calcitonin, and any variants or fusion proteins thereof.

[0016] The term "FGF-18 compound" or "FGF-18" as used herein means a protein that maintains at least one biological activity of the wild-type human FGF-18 protein (e.g., increases osteoblast activity (see WO98 / 1664) or increases chondrogenesis (see WO2008 / 023063)). FGF-18 can be in its native (corresponding to the amino acid sequence from residue 28 (Glu) to residue 207 (Ala) of SEQ ID NO: 1) mature form, or its cleaved form (such as spri-fermin; having the amino acid residues 2 to 170 of SEQ ID NO: 2 corresponding to amino acid residues 28 to 196 of SEQ ID NO: 1) as shown in SEQ ID NO: 2). The term "FGF-18 compound" includes, in addition to variants or mutants of the native mature or cleaved form of FGF-18, fusion proteins (such as those disclosed in the EP17192467.3 patent family) that contain a (bio)active FGF-18 moiety coupled to a heterologous protein or compound. In such fusion proteins, the FGF-18 moiety can be the native mature or cleaved form of FGF-18, or variants or mutants thereof.

[0017] The term "calcitonin" as used herein means the type of calcitonin from salmon. This is a peptide consisting of 32 amino acids (SEQ ID NO: 3) and has been demonstrated to have protective activity against both bone and cartilage.

[0018] The term "BMP-2" as used herein refers to a protein that promotes matrix synthesis to facilitate cartilage repair and plays a crucial role in the differentiation of bone progenitor cells into osteoblasts, thus promoting bone and cartilage formation (Deng et al., 2018). The full-length native form of human BMP-2 is represented by SEQ ID NO: 4. One recombinant form of the BMP-2 protein is known as dibotermin alpha. The term "BMP-2" also includes its variants or fusion proteins containing the BMP-2 moiety.

[0019] The term "BMP-7" as used herein refers to a protein known for its bone-forming properties and has been shown to have a potent anabolic effect on cartilage by promoting the synthesis of cartilage matrix components and increasing the synthesis of proteoglycans and collagen (Deng et al., 2018). The full-length native form of human BMP7 is represented by SEQ ID NO: 5. One recombinant form of the BMP-2 protein is known as eptotermin alpha. This term also includes its variants or fusion proteins containing the BMP-7 moiety.

[0020] The term "GDF-5", also known as LAP-4 or radotermin, as used herein refers to a protein that is derived from both healthy subjects and OA patients and specifically has a promoting effect on matrix synthesis in human articular chondrocytes cultured in vitro (Parrish et al., 2017). The full-length native form of human GDF-5 is represented by SEQ ID NO: 6. This term also includes its variants or fusion proteins containing the GDF-5 moiety.

[0021] The terms "FGFβ" or "FGF-2" as used herein mean a protein known for cartilage repair. It has also been shown to promote chondrocyte proliferation in immature rabbits (Ameye and Young, 2006). The full-length native form of human FGF-2 is represented by SEQ ID NO: 7. One recombinant form of the FGFβ protein is known as trafermin. This term also includes its variants, or fusion proteins containing the FGFβ moiety.

[0022] The term "FGF-9" as used herein means a protein that is known to delay the deterioration of articular cartilage in OA subjects while having a somewhat negative effect on osteophyte formation (Zhou et al., 2016). The full-length native form of human FGF-9 is represented by SEQ ID NO: 8. This term also includes its variants, or fusion proteins containing the FGF-9 moiety.

[0023] The term "TGF-β" as used herein means the protein TGF-beta belonging to the TGF-beta family, which plays an extremely important role in cartilage maintenance. TGF-β has been shown to be a cartilage enhancer (Wang, 2014). This term also includes its variants, or fusion proteins containing the TGF-β moiety.

[0024] The term "SOX-9 enhancer" as used herein is assumed to mean a compound that enhances the production of SOX9. In fact, SOX9 is a transcription factor that has been shown to be essential for the formation of the chondrocyte extracellular matrix (ECM).

[0025] The term "Wnt inhibitor" as used herein is assumed to mean a compound that interferes with the WNT pathway.

[0026] The term "anti-MMP13 inhibitor" as used herein is assumed to mean a compound that inhibits the activity of matrix metalloproteinase 13 (MMP13). MMP13 is one of the important collagen type II degrading enzymes.

[0027] The term "anti-ADAMTS4 inhibitor or anti-ADAMTS5 inhibitor" is herein assumed to mean a compound that inhibits the enzymatic activity of a disintegrin and metalloproteinase having thrombospondin motif 4 or 5 (ADAMTS4 or ADAMTS5).

[0028] The term "SD" means standard deviation and is associated with the normal deviation of any validation assay / system.

[0029] The term "cartilage disorder" as used herein encompasses disorders resulting from injuries caused by damage (such as traumatic injury, osteomalacia, or arthritis). Non-limiting examples of cartilage disorders that may be treatable by administration of the compounds described herein include arthritis (such as osteoarthritis), cartilage injury, fractures affecting articular cartilage, or surgical procedures affecting articular cartilage (such as microfracture). Degenerative diseases / disorders of cartilage or joints (such as chondrocalcinosis, polychondritis, relapsing polychondritis, ankylosing spondylitis, or costochondritis) are also encompassed by this term. The International Cartilage Repair Society has proposed an arthroscopic evaluation system for assessing the severity of cartilage defects. That is, grade 0: (normal) healthy cartilage, grade 1: cartilage having soft spots or blisters, grade 2: small fissures visible in the cartilage, grade 3: deep fissures in the lesion area (more than 50% of the cartilage layer), and grade 4: fissures in the cartilage exposing the underlying (subchondral) bone (see, for example, page 13 of www.cartilage.org / _files / contentmanagement / ICRS_evaluation.pdf).

[0030] The term "osteoarthritis" is assumed herein to mean the most common form of arthritis. The term "osteoarthritis" encompasses both primary osteoarthritis and secondary osteoarthritis (see, e.g., The Merck Manual, 17th Edition, page 449). The most common way to classify / grade osteoarthritis is by use of the Kellgren-Lawrence X-ray assessment scale (see table below). Osteoarthritis can be caused by the destruction of cartilage. Pieces of cartilage can break off and cause pain and swelling in the joints between bones. Over time, the cartilage wears away completely and the bones rub against each other. Osteoarthritis can affect any joint, but usually affects the hands and the weight-bearing joints (hip, knee, leg, spine). In a preferred example, osteoarthritis can be osteoarthritis of the knee or osteoarthritis of the hip. Osteoarthritis is one of the preferred cartilage disorders that can be treated by administering a compound according to the present invention.

[0031] The Kellgren-Lawrence (KL) X-ray assessment scale for osteoarthritis is described below.

[0032] [Table 1]

[0033] Grades 1 and 2 can be regarded as the less severe forms of the disease, whereas grades 3 and 4 can be regarded as the more severe forms of the disease.

[0034] The term "cartilage injury" means, herein, a cartilage disorder or cartilage damage, which as a result can lead in particular to further accidents or surgeries (e.g., microfracture surgery). This term "cartilage injury" includes fractures of cartilage or osteochondral fractures, injuries to the meniscus, and the term microfracture. Also taken into account in this definition are sports-related injuries or sports-related wear of the joint tissue.

[0035] As used herein, the term "joint space width (JSW)" means the joint space width measured by X-ray using a standardized technique (such as a fixed flexion protocol as disclosed by Hunter et al. in 2009). The measurement of JSW by X-ray is an approved endpoint accepted by the European Medicines Agency and the United States Food and Drug Administration for use in the study of effects in OA. As used herein, the term "medial joint space width (mJSW)" means the joint space width measured by X-ray in the medial compartment of a joint (particularly the knee). As used herein, the term "lateral joint space width (lJSW)" means the joint space width measured by X-ray in the lateral compartment of a joint (particularly the knee). As used herein, the term "minimum joint space width (miniJSW)" means the minimum joint space width measured by X-ray in either the medial or lateral compartment of a joint (particularly the knee).

[0036] As used herein, the term "thin cartilage" means cartilage with a JSW of 3.5 mm or less.

[0037] As used herein, the term "thick cartilage" means cartilage with a JSW greater than 3.5 mm.

[0038] As used herein, the term "progression of cartilage damage" means a structural defect of the cartilage and / or joint affected by cartilage damage, particularly an increase in joint space narrowing (JSN), and as a result of the progression of cartilage damage over time, clinical symptoms (such as pain, physical impairment, and joint stiffness) appear or increase. With respect to OA, the progression of this disorder can be observed and evaluated, for example, using the KL assessment scale defined above.

[0039] As used herein, the expression "at risk of further structural and symptomatic progression of cartilage damage" also means "at risk of rapid progression of cartilage damage" as used in the context of a subject to be treated, and means that the subject has a tendency to exhibit rapid progression of cartilage damage as a result of the natural progression of this disorder over time without treatment. Thus, these expressions exclude structural progression of cartilage damage that is thought to be due to trauma or injury that is not a result of cartilage damage.

[0040] The terms "subject" or "patient" both mean human and non-human animals. The term non-human includes mammals (such as rodents (including mice), rabbits, cats, dogs, horses, cows, sheep, primates, etc.).

[0041] The expression "significant structural defect of the joint" in this specification means a structural defect of the joint, such as a significant minimum joint space width (miniJSW) or a significant KL grade, especially a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3. More preferably, the preferred significant structural defect of the joint is the minimum joint space width (miniJSW) of 1.5 mm to 3.5 mm.

[0042] The expression "intolerable joint pain" in this specification means that the pain of the joint is at a significant level. The pain level can be evaluated using methods generally used in this field, especially in the context of clinical trials of OA patients. Non-limiting examples of such methods include the NRS score, VAS pain score, KOOS score, and WOMAC pain score, which are methods for measuring outcomes reported by patients and defined below.

[0043] In the context of the present invention, a WOMAC pain score of 35 or more, preferably 40 or more, indicates intolerable joint pain.

[0044] In the context of the present invention, a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale) indicates intolerable joint pain (Williamson et al., 2005).

[0045] In the context of the present invention, an NRS score of 4 or more (on a scale of 0 - 11) indicates intolerable joint pain (Williamson et al., 2005).

[0046] In the context of the present invention, a KOOS score of 40 or more (on a scale of 0 to 100) indicates intolerable joint pain (Roos et al., 2003).

[0047] The "WOMAC Index" means, in this specification, the WOMAC® 3.1 Index (where "WOMAC" means the 3.1 version of the "Western Ontario and McMaster Universities Osteoarthritis Index"). This index is a self-administered questionnaire that assesses three dimensions of pain in osteoarthritis of the knee and hip, namely pain, physical disability, and joint stiffness. When applied to the assessment of pain and dysfunction associated with cartilage damage, it consists of a questionnaire containing 24 items (5 items related to pain, 2 items related to stiffness, and 17 items related to physical function) (see Bellamy et al., 1988; Wolfe, 1999). This is a well-known tool widely used, particularly in the assessment of the severity of OA. The latest version of this tool (WOMAC® 3.1) can be used in over 100 language forms, allowing easy application to any subject, regardless of their native language.

[0048] The "WOMAC total score" or "WOMAC score" means, in this specification, the sum of scores obtained in a particular patient who answered the WOMAC index questionnaire (where "WOMAC" means "Western Ontario and McMaster Universities Osteoarthritis Index") that measures pain (WOMAC pain score) based on 5 items, function (WOMAC function score) based on 2 items, and stiffness (WOMAC stiffness score) based on 17 items. Each item is scored based on the response (none = 0 points, mild = 1 point, moderate = 2 points, severe = 3 points, extreme = 4 points). The WOMAC total score corresponds to the sum of the points obtained in 24 items. The WOMAC pain score corresponds to the sum of the points obtained in 5 items related to pain, and is subsequently, in some cases, normalized to a scale of 0 to 100 points (i.e., the WOMAC pain score is multiplied by 5). Preferably, in the context of the present invention, the indicated WOMAC pain score corresponds to the WOMAC pain score normalized to a scale of 0 to 100 points. The WOMAC function score corresponds to the sum of the points obtained in 2 items related to function, and is subsequently, in some cases, normalized to a scale of 0 to 100 points (i.e., multiplied by 100 / 8). Preferably, in the context of the present invention, the indicated WOMAC function score corresponds to the WOMAC pain score normalized to a scale of 0 to 100 points. The WOMAC stiffness score corresponds to the sum of the points obtained in 17 items related to function, and is subsequently, in some cases, normalized to a scale of 0 to 100 points (i.e., multiplied by 100 / 68). Preferably, in the context of the present invention, the indicated WOMAC stiffness score corresponds to the WOMAC stiffness score normalized to a scale of 0 to 100 points.

[0049] The "Visual Analogue Scale for Pain (VAS pain)" means, in this specification, a self-administered questionnaire well-known in the art and discussed in detail by Hawker et al.

[0050] The "Numeric Rating Scale for Pain (NRS pain)" means, in this specification, a self-administered questionnaire well-known in the art and discussed in detail by Hawker et al.

[0051] The "Knee injury and Osteoarthritis Outcome Score (KOOS)" means, in this specification, a self-administered questionnaire that includes five separately scored subscales, namely pain, other symptoms, function in activities of daily living (ADL), function in sports and recreation (Sport / Rec), and quality of life (QOL) related to the knee. Preferably, this expression means the use of questionnaires available in different languages, as described in Roos et al., 1998, Roos et al., 2003, Collins et al., 2016.

[0052] The term "chondral thinning" means, in this specification, a decrease in the volume and / or thickness of cartilage as a result of the progression of cartilage damage over time without treatment. In the context of the present invention, chondral thinning can be evaluated by using magnetic resonance imaging (MRI) measurements to measure the thickness of cartilage (including the lateral femoral tibial cartilage (also called LFTC), the medial femoral tibial cartilage (also called MFTC), the total volume of cartilage (also called LFTC+MFTC), and the new total mean of cartilage thickness) at different time points.

[0053] The expression "restricting chondral thinning associated with cartilage damage" regarding the therapeutic effect of the FGF-18 compound means that the chondral thinning over time in the treatment of a subject with the said compound is reduced compared to chondral thinning that occurs or is likely to occur over time without treatment. Chondral thinning that occurs or is likely to occur over time without treatment can be evaluated, for example, based on the results of clinical trials.

[0054] The expression "preventing chondral thinning associated with cartilage damage", when describing the therapeutic effect of the FGF-18 compound, means that the chondral thinning over time in the treatment of a subject with the said compound is suppressed compared to the thickness of the subject's cartilage before the treatment.

[0055] The expression "clinical symptoms associated with cartilage damage" means, in this specification, the clinical symptoms (pain, physical disability, and joint stiffness) that are the result of cartilage damage. The clinical symptoms associated with the progression of cartilage damage and the clinical symptoms associated with the progression of cartilage damage can be evaluated using the WOMC index defined in this specification.

[0056] Pain can be evaluated by the WOMAC pain score. A WOMAC pain score of 20 or more indicates moderate to severe pain, while a WOMAC pain score of 35 or more indicates intolerable pain (Goggins et al., 2005). Similarly, physical disability and joint stiffness can be evaluated by the WOMAC function score and the WOMAC stiffness score, respectively.

[0057] The expression "clinical symptoms associated with the progression of cartilage damage over time" means, in this specification, the symptoms that occur over time as a result of the natural progression of cartilage damage without treatment, including increasing pain, increasing physical disability, and increasing joint stiffness. An increase in the WOMAC index over time indicates an increase in clinical symptoms. In particular, an increase in the WOMAC pain score of a subject over time indicates an increase in pain. Similarly, an increase in the WOMAC function score and the WOMAC stiffness score over time indicates an increase in physical disability and joint stiffness, respectively.

[0058] The expressions "limiting the clinical symptoms associated with cartilage damage" and "limiting the clinical symptoms associated with the progression of cartilage damage over time" regarding the therapeutic effect of the FGF-18 compound mean that the clinical symptoms defined above in the subject treated with the compound decrease over time compared to the clinical symptoms without treatment.

[0059] The term "SD" means standard deviation and is associated with the normal deviation of any validation assay / system.

[0060] The term "placebo" means, in this specification, a compound or composition lacking any therapeutic activity.

[0061] As used herein, the term "placebo effect" should be understood to mean that the administration of a placebo causes a change in a structural defect or clinical symptom as compared to the baseline, i.e., as compared to the structural defect or clinical symptom in the absence of any administration. The term "weak placebo effect" means a response intensity that is equal to or only slightly changed (less than 20%) as compared to the response intensity at baseline. The term "strong placebo effect" should be understood herein to mean a change of more than 20% from baseline.

DETAILED DESCRIPTION OF THE INVENTION

[0062] The surprising finding of the present invention is based on various studies aimed at identifying potential subgroups related to different responses to treatment. The parameters used in these studies consisted of imaging techniques and measurements of outcomes reported by patients (such as WOMAC scores). JSW measurements were used as imaging markers of structural defects in joints. The relationship between measurements of outcomes reported by patients and / or imaging markers (JSW, changes in clinical symptoms, etc.) and variations in clinical symptoms was evaluated. The reason for performing this type of analysis was to identify combinations of markers that could potentially predict 1) the placebo response and / or 2) the clinical outcome (particularly related to cartilage repair and symptom improvement) for subjects treated with an active compound (e.g., an FGF-18 compound, a BMP-2 enhancer, a BMP-7 enhancer, a GDF-5 enhancer, an FGFβ enhancer, an FGF-9 enhancer, a SOX-9 enhancer, a TGFβ inhibitor, a Wnt inhibitor, an anti-MMP-13 inhibitor, an anti-ADAMTS4 inhibitor or an anti-ADAMTS5 inhibitor, calcitonin, and any variants or fusion proteins thereof). In particular, it was surprisingly found that the placebo effect could be predicted using a combination of structural defects and pain levels (see the experimental section and FIGS. 2 and 3).

[0063] The present invention is based on the finding that among a diverse population affected by OA (particularly knee OA), subjects at risk of further progression of the structure and symptoms of cartilage damage, i.e., subjects at risk of rapid progression of cartilage damage, show a particularly good response to treatment with an active compound (particularly an FGF-18 compound).

[0064] As defined in more detail herein, a patient is considered at risk of rapid progression of cartilage damage when that patient exhibits a combination of the following two parameters: (a) a significant structural defect of the joint and (b) intolerable joint pain.

[0065] Fibroblast growth factor 18 (FGF-18) is a member of the protein FGF family and is closely related to FGF-8 and FGF-17. FGF-18 has been shown to be a proliferator of chondrocytes and osteoblasts (Ellsworth et al., 2002; Shimoaka et al., 2002; Gigout et al., 2017). FGF-18 has been proposed for the treatment of cartilage damage (such as osteoarthritis and cartilage injury) either alone (WO2008 / 023063) or in combination with hyaluronic acid (WO2004 / 032849).

[0066] Sprifermin is a truncated form of human FGF-18 and has been investigated in clinical trials for the treatment of both osteoarthritis and cartilage injury (see, for example, NCT01033994, NCT00911469, and NCT01066871). The current dosing schedule for sprifermin is once a week for 3 weeks (one treatment cycle), and the drug is administered via intra-articular injection. This treatment cycle can be repeated. This dosing schedule is described in WO2008 / 023063.

[0067] Interestingly, in a subgroup of subjects at risk of rapid progression of osteoarthritis (also referred to herein as the at-risk subgroup, at-risk subject, or at-risk patient), treatment with an FGF-18 compound has been shown to limit, and indeed suppress, the progression of cartilage thinning and to limit the clinical symptoms (especially pain) associated with said cartilage damage.

[0068] Interestingly, even 18 months after the last administration of the therapeutic agent, patients from the at-risk subgroup treated with FGF-18 show improvement in clinical symptoms (especially pain) compared to the time of the last injection. In other words, even after treatment has ended, the clinical outcome of the at-risk subgroup of subjects treated with an FGF-18 compound continues to improve. In contrast, during the same period, the at-risk subgroup of subjects treated with placebo shows worsening or increase in clinical symptoms (especially pain). This suggests that the FGF-18 compound significantly improves the clinical outcome in at-risk subjects. Overall, the therapeutic effect obtained with an FGF-18 compound in the at-risk subgroup of subjects defined herein appears to clarify a special clinical situation that has not been investigated before.

[0069] The present invention relates to an active compound for use in a subject having cartilage damage, wherein the subject exhibits a risk of rapid progression of said cartilage damage.

[0070] In the context of the present invention, the active compound is selected from the group consisting of an FGF-18 compound, a BMP-2 enhancer, a BMP-7 enhancer, a GDF-5 enhancer, an FGFβ enhancer, an FGF-9 enhancer, a SOX-9 enhancer, a TGFβ inhibitor, a Wnt inhibitor, an anti-MMP-13 inhibitor, an anti-ADAMTS4 inhibitor or an anti-ADAMTS5 inhibitor, calcitonin, and any variant or fusion protein thereof.

[0071] The active compound is preferably the FGF-18 compound as defined herein.

[0072] In the context of the present invention, a subject is considered to exhibit a risk of rapid progression of cartilage damage when the subject has the following two parameters, namely (a) a significant structural defect of the joint; and (b) an intolerable joint pain in combination.

[0073] In the context of the present invention, the preferred significant structural defects of the joint are selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3. More preferably, the preferred significant structural defect of the joint is a minimum joint space width (miniJSW) of 1.5 mm to 3.5 mm.

[0074] In the context of the present invention, the preferred intolerable joint pain is selected from the group consisting of joint pain corresponding to a WOMAC joint pain score of at least 35 points, preferably at least 40 points, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a 0 - 11 scale), and joint pain corresponding to a KOOS score of 40 or more (on a 0 - 100 scale).

[0075] Preferably, a subject is considered to exhibit a risk of rapid progression of the cartilage damage when the subject has (a) a significant structural defect of the joint selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; and (b) joint pain corresponding to a WOMAC joint pain score of at least 35 points, preferably at least 40 points in combination.

[0076] More preferably, a subject is considered to exhibit a risk of rapid progression of the cartilage damage when the subject has (a) The minimum joint space width (miniJSW) is less than 3.5 mm, preferably 1.5 mm to 3.5 mm, (b) The joint pain corresponding to a WOMAC joint pain score of at least 35 points, preferably at least 40 points is indicated.

[0077] Even more preferably, the subject is considered to exhibit a risk of rapid progression of the cartilage disorder if the subject (a) has a minimum joint space width (miniJSW) of 1.5 mm to 3.5 mm, (b) has joint pain corresponding to a WOMAC joint pain score of at least 40 points is indicated.

[0078] In a preferred embodiment, the present invention relates to an FGF-18 compound for use in the treatment of a subject with a cartilage disorder, and the subject (a) has a minimum joint space width (miniJSW) of 1.5 mm to 3.5 mm, (b) has joint pain corresponding to a WOMAC joint pain score of at least 40 points is indicated.

[0079] The present invention further relates to a method for treating a subject with a cartilage disorder, the method comprising a) determining whether the subject exhibits at least one significant structural defect in at least one joint (wherein the significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3) and; b) obtaining an assessment of the level of joint pain of the subject (wherein the level of joint pain is preferably evaluated based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score) and; c) i. at least one significant structural defect in at least one joint and ii. intolerable joint pain selecting a patient having the same. d) administering an active compound, preferably an FGF-18 compound, to the selected patient.

[0080] In the context of the present invention, a WOMAC pain score of 35 or more, preferably 40 or more, indicates intolerable joint pain.

[0081] In the context of the present invention, a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale) indicates intolerable joint pain.

[0082] In the context of the present invention, an NRS score of 4 or more (on a scale of 0 - 11) indicates intolerable joint pain.

[0083] In the context of the present invention, a KOOS score of 40 or more (on a scale of 0 - 100) indicates intolerable joint pain.

[0084] Preferably, the present invention relates to a method for treating a subject with cartilage damage, the method comprising a) determining whether the subject exhibits at least one significant structural defect in at least one joint, wherein the significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm; b) obtaining an assessment of the level of joint pain in the subject, wherein the level of joint pain is preferably evaluated based on the WOMAC pain score; and c) i. at least one significant structural defect in at least one joint and ii. intolerable joint pain selecting a patient having the same; and d) administering an active compound, preferably an FGF-18 compound, to the selected patient.

[0085] Preferably, in the context of the present invention, the active compound (preferably an FGF-18 compound) for use or in the treatment methods defined above restricts or prevents the progression of cartilage thinning associated with said cartilage disorder. Preferably, in the context of the present invention, the active compound (preferably an FGF-18 compound) for use or in the treatment methods defined above restricts or prevents the clinical symptoms associated with said cartilage disorder. Preferably, the clinical symptoms are selected from the list consisting of pain, movement disorder, and joint stiffness associated with said cartilage disorder. More preferably, the clinical symptom is pain associated with said cartilage disorder. In a preferred embodiment, the clinical symptoms are selected from the list consisting of increasing pain, movement disorder, and joint stiffness associated with the progression of said cartilage disorder. More preferably, the clinical symptom is increasing pain associated with the progression of said cartilage disorder. Preferably, in the context of the present invention, the active compound (preferably an FGF-18 compound) for use or in the treatment methods defined above restricts or prevents the progression of cartilage thinning in a subject and the clinical symptoms associated with said cartilage disorder.

[0086] In another aspect, the present invention relates to an active compound (preferably an FGF-18 compound) for use in preventing or treating clinical symptoms associated with a cartilage disorder in a subject having said cartilage disorder, wherein the subject exhibits a risk of rapid progression of said cartilage disorder. In a preferred embodiment, the clinical symptoms are selected from the list consisting of pain, movement disorder, and joint stiffness associated with said cartilage disorder. More preferably, the clinical symptom is pain associated with said cartilage disorder. In a preferred embodiment, the clinical symptoms are selected from the list consisting of increasing pain, movement disorder, and joint stiffness associated with the progression of said cartilage disorder. More preferably, the clinical symptom is increasing pain associated with the progression of said cartilage disorder.

[0087] In the context of the present invention, preferred cartilage disorders are selected from osteoarthritis, cartilage trauma, fractures affecting articular cartilage, or surgical procedures affecting articular cartilage (such as microfracture). Advantageously, the cartilage disorder is osteoarthritis, preferably osteoarthritis of the knee or hip.

[0088] Preferably, an FGF-18 compound is selected from the group consisting of a natural FGF-18 form (SEQ ID NO: 1), the mature form of natural FGF-18 (corresponding to the amino acid sequence from residue 28 (Glu) to residue 207 (Ala) of SEQ ID NO: 1), a cleaved form of FGF-18 (such as spri-fermin) (corresponding to amino acid residues 2 to 170 of SEQ ID NO: 2 which corresponds to amino acid residues 28 to 196 of SEQ ID NO: 1) (also referred to herein as FGF-18 (170 amino acids)). More preferably, the FGF-18 compound of the present invention is a polypeptide comprising or consisting of a) a human FGF-18 mature form comprising residues 28 to 207 of SEQ ID NO: 1, or b) a polypeptide comprising or consisting of FGF-18 (170 amino acids) (SEQ ID NO: 2), selected from the group consisting of polypeptides.

[0089] Preferably, the FGF-18 compound is administered intra-articularly.

[0090] The FGF-18 compound should be administered according to a suitable dosing regimen at an effective dose, and the dosing regimen can be tailored to the subject by a physician taking into account, for example, gender, age, KL grade, or other subject-specific parameters.

[0091] In a preferred embodiment, the FGF-18 compound is administered at a dose of 1 to 100 μg, or preferably 1 to 60 micrograms (μg), or preferably 3 to 50 μg, or preferably 5 to 40 μg, or preferably 10 to 30 μg each time the FGF-18 compound is administered intra-articularly. In a preferred embodiment, the treatment comprises administering the FGF-18 compound at a dose of about 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 μg each time the FGF-18 compound is administered intra-articularly. Preferred doses include 5, 10, 15, 20, 25, and 30 μg each time the FGF-18 compound is administered intra-articularly.

[0092] In yet another preferred embodiment, the FGF-18 compound is administered at a dose of 50-200 mcg / kg, preferably 80-120 mcg / kg, each time the FGF-18 compound is administered intravenously. In a preferred embodiment, the treatment comprises administering the FGF-18 compound at a dose of 80, 90, 100, 110, or 120 mcg / kg each time the FGF-18 compound is administered intravenously.

[0093] Preferably, the FGF-18 compound is administered according to a dosing schedule comprising at least one treatment cycle consisting of at least two administrations, and the two administrations are separated by 4, 5, 6, 7, 8, 9, or 10 days, preferably 7 days. Preferably, the dosing schedule comprises at least two treatment cycles of at least two administrations, and the treatment cycles are separated by about 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, preferably 6 months.

[0094] In a preferred embodiment, the FGF-18 compound is administered intra-articularly at a dose of 100 μg per injection, once a week for 3 weeks, for each treatment cycle, in a dosing schedule comprising at least two treatment cycles, and the treatment cycles are separated by about 10-14 months, preferably 12 months. In a more preferred embodiment, the FGF-18 compound is administered intra-articularly at a dose of 100 μg per injection, once a week for 3 weeks, for each treatment cycle, in a dosing schedule comprising at least four treatment cycles, and the treatment cycles are separated by about 4-8 months, preferably 6 months.

[0095] The FGF-18 compound can be formulated as a pharmaceutical composition, i.e., formulated together with a pharmaceutically acceptable carrier, excipient, etc. The definition of "pharmaceutically acceptable" means including any carrier, excipient, etc. that does not interfere with the bioactivity effectiveness of the active ingredient and is not toxic to the patient to whom it is administered. For example, in parenteral administration, the active protein can be formulated into a unit dosage form for injection in a vehicle (such as physiological saline, dextrose solution, serum albumin, and Ringer's solution, etc.). The formulation for intra-articular application will likely meet most of the conditions applicable to other injection formulations. That is, these formulations need to be sterile and compatible with the physiological conditions at the application site (such as the knee joint, synovial fluid). For example, for intramuscular or subcutaneous application, the excipients used in intra-articular injection can also be present in other injection formulations. Such a formulation of the FGF-18 compound, including at least one further different carrier, excipient, etc. that is pharmaceutically acceptable, is also referred to herein as an "FGF-18 composition" or an "FGF-18 formulation". The above-mentioned "FGF-18 composition" or "FGF-18 formulation" is also useful in the context of this specification.

[0096] The present invention further relates to a method for selecting a subject having a cartilage disease for inclusion in a treatment or clinical trial using an active compound, based on the likelihood that they are sensitive to the treatment, the method comprising: a) determining whether the subject exhibits at least one significant structural defect in at least one joint (wherein the significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3); and b) obtaining an assessment of the level of joint pain in the subject (wherein the level of joint pain is preferably evaluated based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score); and c) selecting the sensitive patient as being suitable for the treatment or clinical trial.

[0097] Preferably, according to the method, a) a significant structural defect selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) intractable joint pain selected from the group consisting of joint pain corresponding to a WOMAC joint pain score of at least 35 points, preferably at least 40 points, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a 0-11 scale), and joint pain corresponding to a KOOS score of 40 or more (on a 0-100 scale) the presence of indicates that the subject is sensitive to the treatment.

[0098] The present invention further relates to a method for determining a placebo effect in a clinical trial (preferably, the clinical trial relates to treating a cartilage disorder of a subject with an active compound), or a placebo effect during treatment of a cartilage disorder with an active compound, the method comprising a) determining whether the subject exhibits at least one significant structural defect in at least one joint, wherein the significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) obtaining an assessment of the level of joint pain of the subject, wherein the level of joint pain is preferably evaluated based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score; c) determining the placebo effect from the results of steps a) and b).

[0099] Preferably, according to the method, a) A significant structural defect selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) Intolerable joint pain selected from the group consisting of joint pain corresponding to a WOMAC joint pain score of at least 35 points, preferably at least 40 points, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a 0 - 11 scale), and joint pain corresponding to a KOOS score of 40 or more (on a 0 - 100 scale) The presence of predicts a small placebo effect.

[0100] More preferably, according to the method, a minimum JSW of more than 3.5 mm and a WOMAC pain score of less than 35 points, preferably less than 40 points, predicts a strong placebo effect. Conversely, a minimum JSW of 3.5 mm or less and a WOMAC pain score of less than 35 points, preferably less than 40 points, predicts no placebo effect or a weak placebo effect.

Brief Description of the Drawings

[0101]

Figure 1

[0102]

Figure 2

[0103]

Figure 3

[0104]

Figure 4

[0105]

Figure 5

[0106]

Figure 6

[0107]

Figure 7

[0108] Description of sequences:

[0109] SEQ ID NO: 1: Amino acid sequence of native human FGF-18.

[0110] SEQ ID NO: 2: Amino acid sequence of recombinant cleaved FGF-18 (trFGF-18).

[0111] SEQ ID NO: 3: Amino acid sequence of salmon calcitonin.

[0112] SEQ ID NO: 4: Amino acid sequence of human BMP-2.

[0113] SEQ ID NO: 5: Amino acid sequence of human BMP-7.

[0114] SEQ ID NO: 6: Amino acid sequence of human GDF-5.

[0115] SEQ ID NO: 7: Amino acid sequence of human FGFβ.

[0116] SEQ ID NO: 8: Amino acid sequence of human FGF-9.

Examples

[0117] Statistical method

[0118] Repeated measures analysis of variance (ANOVA, using PROC MIXED in SAS) for absolute changes from baseline was utilized to evaluate the treatment effect on the primary endpoint by varying the dose (with baseline value, treatment group, time, and country included as factors and treatment by timepoint included as an interaction). The analysis of the main effects consisted of examining the linear dose relationship and overall treatment effect at the 2-year timepoint. The significance level was set at 5% two-sided for both tests. Pairwise comparisons (sprifermin versus placebo and between sprifermin doses and treatment groups) were performed within the context of this modeling framework. For each pairwise comparison, the difference between treatments, corresponding 95% confidence interval (CI), and p-value were presented. The same ANOVA model used for the primary endpoint was utilized to evaluate the treatment effect and changes over time at each timepoint for continuous secondary endpoints (MRI endpoints, WOMAC endpoints (total score, pain score, function score, and stiffness score), radiographic endpoints, etc.). Logistic regression was used to compare the treatment effect for binary efficacy endpoints (such as OMERACT-OARSI response rate). Point estimates, corresponding 95% CIs, and p-values for each pairwise comparison were presented.

[0119] Assessment of pain and function

[0120] WOMAC is a validated tool used to assess changes in symptoms in clinical OA research. This clinical score was developed in 1981 and is considered a valid tool by both clinical researchers and regulatory authorities. WOMAC is widely used in clinical research in OA of the hip and knee joints and has been extensively validated.

[0121] For the examples, the subjects were asked to self-respond to all 24 questions (i.e., 5 regarding pain, 2 regarding stiffness, and 17 regarding physical function assessment) using an 11-box NRS assessment (category from 0 to 10) with reference to the past 48 hours for Example 1 and a 100 mm VAS (Visual Analogue Scale; scores from 0 to 100 for each question) with reference to the past 24 hours for Example 2. Different forms of questionnaires exist for the left and right knees. To minimize the confusion of WOMAC responses due to the symptoms of the contralateral knee, the subjects used a WOMAC questionnaire specialized for the targeted knee.

[0122] For administering the questionnaire, in both Examples 1 and 2, the instructions for the WOMAC 3.1 index were followed.

[0123] Another tool for evaluating pain and function is KOOS (Knee Injury and Osteoarthritis Outcome Score, Collins et al., 2016).

[0124] X-ray assessment of JSW

[0125] The change in JSW measured by X-ray is an accepted endpoint by the European Medicines Agency and the US Food and Drug Administration for use in effect studies in OA. JSW was measured using a standardized technique. X-ray was also used to evaluate the KL grade.

[0126] qMRI assessment

[0127] The primary endpoint for the DBPC treatment phase was the change from baseline in cartilage thickness in the total femorotibial joint, evaluated at the 2-year time point in the mITT. The cartilage thickness of the total femorotibial joint was calculated in two ways: 1. Average cartilage thickness (total volume divided by total surface area) 2. Total cartilage thickness (sum of cartilage thickness in the medial and lateral compartments).

[0128] Repeated measures analysis of variance (ANOVA) for absolute changes from baseline was utilized to evaluate the treatment effect on the primary endpoint by varying the dose (with treatment group, time point, and (pooled) country included as fixed factors, baseline value included as a covariate, and treatment by time point included as an interaction). Repeated measures over time were explained by the use of an “unstructured” covariate pattern.

[0129] Pairwise comparisons of the absolute changes from baseline in cartilage thickness (treatment groups using the compound vs placebo) were performed within the context of the above modeling framework. For each pairwise comparison, the difference between treatments, corresponding 95% confidence intervals (CIs), and p-values are presented. For all combinations of time points (i.e., baseline value, treatment, time point, treatment by time point interaction, country) and for all time points, p-values (corresponding to the Type 3 test of the fixed effects) of all covariates in the original “overall” model are reported. Estimated coefficients, p-values, and 95% CIs for the overall and each time point are presented for (i) the dose relationship (linear trend) and (ii) each pairwise comparison between dose levels and placebo.

[0130] To evaluate the robustness of the primary results, the PP analysis set was utilized and tests regarding the linear dose relationship and overall treatment effect were repeated. For the mITT analysis set, as an alternative method for the primary analysis, a non-parametric analysis of the ordered data of cartilage thickness in the entire femorotibial joint was performed. The data were ordered by the magnitude of the absolute change from baseline over the two-year period during the DBPC treatment phase using rank transformation.

[0131] Example 1: Clinical Effects on Total Cartilage Thickness, Pain, and Function in Subjects Treated with FGF-18 as Measured by MRI and WOMAC Total Score

[0132] The FGF-18 compound used as a therapeutic agent in this example was spri-fermin (as defined in the "Definitions" section). Two strengths of spri-fermin were supplied for the study, namely 30 μg and 100 μg. Spri-fermin was supplied as a white, sterilized lyophilized powder in 3 ml glass vials. Each vial contained 31.5 μg or 105 μg of spri-fermin active substance, and because these amounts included a 5% excess, 30 μg or 100 μg of spri-fermin active substance could be extracted after reconstitution using 0.9% w / v sodium chloride injection solution (referred to herein as "physiological saline solution"). The excipients of the formulation were sodium phosphate buffer (pH 7.2), sodium hydroxide, O-phosphonic acid, sucrose, and poloxamer 188. For all treatment groups, the administered volume was 2 ml.

[0133] This study was based on a prospective study (see study EMR700692-006).

[0134] This study enrolled adult subjects of either sex who had primary femorotibial OA according to the American College of Rheumatology (ACR) clinical and radiographic criteria, with a Kellgren-Lawrence Grade (KLG) of 2 or 3, and a minimum joint space width (JSW) of 2.5 mm or more across the entire knee. Subjects must have had pain in the targeted knee on the majority of days, and / or must not have required treatment with paracetamol (acetaminophen) (a systemic non-steroidal anti-inflammatory drug (NSAID) that includes COX inhibitors (COXibs)) or tramadol for knee pain symptoms on the majority of days in the previous month, and moreover, after at least a 5 half-life washout of analgesics: acetaminophen (local or oral systemic NSAIDs), COXibs, opioids, and / or tramadol, at screening and baseline, 1) must have had a pain history due to OA in the targeted knee for at least 6 months, and 2) must have had both a pain score of 4 - 9 on the answer to question 1 of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain index (\"How much pain did you have [in the targeted knee over the past 48 hours] while walking on a flat surface?\"). Women of childbearing potential must have been using contraception with a failure rate of less than 1% per year through the study institution.

[0135] The main exclusion criteria included malalignment of the femorotibial axis of the targeted knee of more than 5 degrees, clinical signs of inflammation (i.e., redness) in the targeted knee, intra-articular administration of corticosteroids or hyaluronic acid to either knee within 6 months before screening, any planned knee surgery (affecting the targeted knee or the contralateral knee) within the next 2 years, any complications or treatments that were thought to be incompatible with participation in the study, any contraindication to MRI scanning (including inability to fit into the scanner or knee coil), being pregnant or breastfeeding, having participated in another clinical trial within the past 30 days, and being legally incompetent or having limited legal capacity.

[0136] Written informed consent had to be obtained before any activity related to the study.

[0137] Five groups of patients were examined: · Group 1 (4 cycles of placebo; hereafter referred to as placebo or PBO): 108 subjects. · Group 2 (alternating 2 cycles of 30 μg of sprifermin / injection and 2 cycles of placebo; hereafter referred to as sprifermin / placebo 30 μg × 2): 110 subjects. · Group 3 (4 cycles of 30 μg of sprifermin / injection; hereafter referred to as sprifermin 30 μg × 4): 111 subjects. · Group 4 (alternating 2 cycles of 100 μg of sprifermin / injection and 2 cycles of placebo; hereafter referred to as sprifermin / placebo 100 μg × 2): 110 subjects. · Group 5 (4 cycles of 100 μg of sprifermin / injection; hereafter referred to as sprifermin 100 μg × 4): 110 subjects.

[0138] According to this prospective study, patients received 4 cycles of treatment at 6 - month intervals (each consisting of 3 intra - articular injections once a week for 3 consecutive weeks) over a period of 6 months (see Figure 1). All injections were intra - articular (administered into the joint).

[0139] The primary efficacy endpoint was the change from baseline in cartilage thickness in the entire femoral - tibial joint as evaluated by MRI at the 104 - week (2 - year) time point.

[0140] The exploratory endpoints included response to treatment or disease progression (response evaluated by MRI and / or the WOMAC index questionnaire).

[0141] Effect of suprofen on WOMAC pain in different subpopulations based on differences in baseline parameters of patients included in the study

[0142] As is clear from Figure 2, subjects treated with sprifermin and subgrouped based on differences in baseline measurements responded differently with respect to symptoms, as judged by WOMAC pain measurement. In all drawings, mJSW means the minimum joint space width across the knee.

[0143] Effect of suprofen on WOMAC pain in different subpopulations based on JSW of patients included in the study:

[0144] As is clear from Figure 3, subjects treated with sprifermin and subgrouped based on differences in measurements responded differently with respect to symptoms, as judged by WOMAC pain measurement. Patients with a larger minimum JSW had a preference for the placebo response. In contrast, patients with a minimum JSW between 1.5 ± 2 SD mm and 3.5 ± 2 SD mm experienced positive pain relief, as indicated by the reduced WOMAC pain score. The at-risk subgroup (first row) preferred sprifermin and received the greatest average effect. In all drawings, mJSW means the minimum joint space width across the knee.

[0145] Effect of placebo and suprofen on cartilage thickness in the entire population of patients included in the study As is clear from Figure 4A, subjects treated with placebo experienced loss of cartilage thickness during the first 18 months of the study when the placebo was injected and 18 months after the last injection (in contrast, subjects treated with an injection of sprifermin (sprifermin 100 μg × 4) experienced an increase in cartilage thickness during the treatment period. In these subjects, cartilage thickness decreased after the last injection of the sprifermin compound, but cartilage loss remained significantly less in subjects treated with FGF-18 compared to those treated with placebo over the entire duration of the study (0.05 mm, p-value 0.025), indicating that cartilage thinning is limited in all subjects treated with FGF-18.

[0146] Effect of placebo and suprofen on cartilage thickness in at-risk subjects (minimum JSW of 1.5 - 3.5 mm and WOMAC pain score of 40 - 90 points):

[0147] As is apparent from Figure 4B and as expected, patients at risk and treated only with placebo experienced an increase in cartilage loss compared to placebo in the overall study population (the average change in cartilage thickness at 156 weeks compared to baseline in this group was 0.07 mm; see Figure 1A). In contrast, subjects at risk and treated with sprifermin injection (sprifermin 100 μg × 4) experienced limited loss of cartilage thickness during the treatment period (the average change in cartilage thickness at 156 weeks compared to baseline in this group was 0.03 mm). Thus, despite the tendency of subjects at risk of rapid progression of this disease, the benefit of sprifermin with respect to limiting cartilage thinning was observed in the overall OA population in this study. In all drawings, mJSW means the minimum joint space width across the knee.

[0148] Effect of placebo and suprofen on WOMAC total score and pain score in the entire population of patients included in the study

[0149] As is apparent from Figure 5A, the change in the WOMAC global score was not statistically different between subjects treated with placebo and those treated with sprifermin, whether during the first 18 months when injected or after the last injection. In all drawings, mJSW means the minimum joint space width across the knee.

[0150] Effect of suprofen on WOMAC total score in at-risk subjects (minimum JSW of 1.5 - 3.5 mm and WOMAC pain score of 40 - 90 points)

[0151] As is apparent from FIG. 5B, the change in the WOMAC total score was statistically different in the subjects treated with sprifermin (sprifermin 100 μg×4) compared to placebo, or compared to subjects treated with placebo, even by the end of the study (156 weeks), and thus despite the fact that the last injection was administered at 78 weeks. It was unexpected that the clinical symptoms measured by the WOMAC score in the treated subjects were thus improved compared to placebo. This is because these subjects were characterized by intolerable pain at baseline and were expected to progress more rapidly to a more severe stage. Interestingly, in the treated subjects, the WOMAC total score continued to improve after the last injection (negative change in the WOMAC total score), whereas the subjects treated with placebo experienced a relative increase in clinical symptoms (as can be seen from the change in the WOMAC total score between 78 weeks and 156 weeks in these subjects) over the same period. This may reflect an indirect effect of sprifermin on the clinical symptoms of OA, at least for this particular subgroup. In all drawings, mJSW means the minimum joint space width across the knee.

[0152] Effect of suprofen on WOMAC total score in at-risk subjects

[0153] As is apparent from FIGS. 6 and 7, the degree of the effect of sprifermin on the WOMAC total score in subjects at risk as defined herein is greater than in subjects showing a minimum JSW of 1.5 - 3.5 mm at baseline or a WOMAC pain score of 40 or more. This further suggests that the effect on the observed clinical symptoms is particularly improved in subjects at risk of this disease progressing particularly rapidly. In all drawings, the term mJSW means the minimum joint space width across the knee.

[0154] References 1) WO2008 / 023063 2) WO2004 / 032849 3) WO2014 / 023703 4) http: / / www.cartilage.org / _files / contentmanagement / ICRS_evaluation.pdf 5) Lotz, 2010, Arthritis research therapy, 12:211 6) Guermazi et al., 2015, Osteoarthritis Cartilage; 23(12): 2191-2198. 7) Pelletier et al., 2007, Arthritis Res Ther. 9(4):R74. 8) Wang et al., 2018, Arthritis Res Ther. 20: 250. 9) Ellsworth et al., 2002, Osteoarthritis and Cartilage, 10: 308-320 10) Shimoaka et al., 2002, J. Bio. Chem. 277(9):7493-7500 11) Gigout et al., 2017, Osteoarthritis and Cartilage, Osteoarthritis and Cartilage, 25(11):1858-1867. 12) The Merck Manual, 17th edition, page 449 13) Bellamy et al., 1988, J. Rheumatology, 15:1833-1840 14) Wolfe, 1999, Rheumatology, 38:355-361 15) Hunter et al., 2009, Curr Opin Rheumatol.;21(2):110-7. 16) Hawker et al., 2011, Arthritis Care & Research, 63(S11):S240-S252. 17) Williamson et al., 2005, J Clin Nurs.;14(7):798-804. 18) Roos et al., 2003, Health Qual Life Outcomes;1:17. 19) Collins et al., 2016, Osteoarthritis Cartilage. 24(8):1317-29. 20) Roos et al., 1998, Scand J Med Sci Sports.;8(6):439-48.

Claims

Claim 1 A pharmaceutical composition comprising an FGF-18 compound for use in the treatment of a subject having a cartilage disorder, wherein the subject has (a) a significant structural defect of a joint, where the significant structural defect of the joint is selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm and a KL grade of 2-4; (b) intolerable joint pain, where the intolerable joint pain is joint pain corresponding to a WOMAC joint pain score of at least 35 points, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a 0-11 scale), and joint pain corresponding to a KOOS score of 40 or more (on a 0-100 scale), and is selected from the group consisting of; when showing the subject shows a risk of rapid progression of the cartilage disorder, and the FGF-18 compound comprises a) residues 28-207 of SEQ ID NO: 1 or b) SEQ ID NO: 2, a pharmaceutical composition. Claim 2 A pharmaceutical composition comprising an FGF-18 compound for use in the prevention or treatment of clinical symptoms associated with a cartilage disorder in a subject having a cartilage disorder, wherein the subject has (a) a significant structural defect of a joint, where the significant structural defect of the joint is selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm and a KL grade of 2-4; (b) intolerable joint pain, where the intolerable joint pain is joint pain corresponding to a WOMAC joint pain score of at least 35 points, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a 0-11 scale), and joint pain corresponding to a KOOS score of 40 or more (on a 0-100 scale), and is selected from the group consisting of; when showing the subject shows a risk of rapid progression of the cartilage disorder, and the FGF-18 compound comprises a) residues 28-207 of SEQ ID NO: 1 or b) SEQ ID NO: 2, a pharmaceutical composition. Claim 3 The pharmaceutical composition according to claim 2, wherein the clinical symptoms are selected from the list consisting of pain, physical impairment, and joint stiffness associated with the cartilage disorder. Claim 4 The pharmaceutical composition according to claim 3, wherein the clinical symptom is pain associated with the cartilage disorder. Claim 5 The pharmaceutical composition according to any one of claims 1 to 4, wherein the joint disorder is selected from the group consisting of osteoarthritis, cartilage injury, fractures affecting articular cartilage, and surgical procedures affecting articular cartilage.

6. The pharmaceutical composition according to claim 5, wherein the joint disorder is osteoarthritis.

7. The pharmaceutical composition according to claim 6, wherein the joint disorder is osteoarthritis of the knee or hip.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is administered into the joint.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered according to an administration schedule comprising at least one treatment cycle consisting of at least two administrations, and the two administrations are spaced about 4, 5, 6, 7, 8, 9, or 10 days apart.

10. The pharmaceutical composition according to claim 9, wherein the two administrations are spaced about 7 days apart.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is administered into the joint at a dose of 100 μg per injection once a week for 3 weeks in one treatment cycle in an administration schedule comprising at least four treatment cycles, and the treatment cycles are spaced about 4 to 8 months apart.

12. The pharmaceutical composition according to claim 11, wherein the four treatment cycles are spaced about 6 months apart.

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